1. Microbiota-targeted approaches to resolve dysbiosis-induced AD neuropathology following brain injury.

This study aims to investigate the mechanistic linkage between gut microbiota and Alzheimer’s disease (AD) progression following brain trauma and to explore potential interventions strategies, based on four key ideas: 1) brain damage aggravates the pathology of dementia and AD, 2) the cascade triggered after brain injury causes intestinal damage, inflammation and changes in the microbiota, 3) microbiome dysbiosis produces an increase in toxic gut metabolites that aggravate AD pathology, 4) by correcting and restoring the gut microbiota, we are modulating one of the main regulatory pathways of the immune response, and therefore, we are peripherally protecting the brain from consequent neurodegenerative processes. TBI accelerates AD pathology, and gut bacteria mediate this acceleration. We will characterize the impact of antibiotics (ABX) on AD pathology after TBI and further explore how restoring the AD gut microbiome after TBI can reduce the inflammatory response and Aβ accumulation in the brain and modulate motor deficits and cognition.

2. The Role of Peripheral Inflammation on Brain Damage in a Sex-Dependent manner.

Traumatic Brain Injury (TBI) and cerebral ischemia trigger a loss of brain tissue and, subsequently, a strong inflammatory response in the brain. In addition, brain damage can alter the function of peripheral regions and other organs, eliciting systemic responses, and global consequences. A focal injury to the brain elicits a rapid hepatic response; the production of chemokines by the liver acts as an amplifier of the focal injury response providing a route of CNS-liver communication. However, little is currently known regarding the inflammatory mediators and acute-phase proteins involved in the peripheral regions after brain injury, such as the liver. Furthermore, the extent of damage TBI inflicts on the peripheral organs remains largely unexplored.

3. Gut microbiota diagnostic for Concussions in athletes who play contact sports.

Athletes who participate in contact sports are at risk of suffering from concussions, which can result in chronic headaches, nausea, anxiety and depression. Head injury also induces intestinal changes, including to microbes found in the gut; and the brain, in turn, can react to signals from the intestinal microbiome. This interaction is called the “brain-gut” axis. The results from this study will help us to identify temporal sequelae and biomarkers of head injury and will lead us to new treatments to prevent the consequences of concussions.

Selected publications:

Alterations to the gut microbiome after sport-related concussion in a collegiate football players cohort: A pilot study. Soriano S, Curry K, Sadrameli SS, Wang Q, Nute M, Reeves E, Kabir R, Wiese J, Criswell A, Schodrof S, Britz GW, Gadhia R, Podell K, Treangen T, Villapol S. Brain Behav Immun Health. 2022 Mar 1;21:100438. doi: 10.1016/j.bbih.2022.100438. eCollection 2022 May. PMID: 35284846

4. Biomimetic Nanoparticles as a Theranostic tool for Brain Injury and Alzheimer’s disease.

Biomimetic nanoparticles serve as a dual-purpose theranostic tool for brain injury and Alzheimer’s disease, combining treatment and diagnosis. Nanoparticles (NPs) have been used in multiple diseases as drug delivery tools with remarkable success due to their rapid diffusion and specificity in the target organ. They are designed to imitate natural biological systems, which improves their integration into the brain’s cellular framework. These nanoparticles can deliver targeted therapies while providing diagnostic imaging, offering a personalized and efficient approach to manage and monitor neurodegenerative conditions. We will use animal models of TBI and AD.

Selected publications: Biomimetic Nanoparticles as a Theranostic Tool for Traumatic Brain Injury. Zinger A, Soriano S, Baudo G, De Rosa E, Taraballi F, Villapol S. Adv Funct Mater. 2021 Jul 23;31(30):2100722. doi: 10.1002/adfm.202100722. Epub 2021 Mar 26. PMID: 34413716.

5. Intranasal Delivery of Telomerase Reverse Transcriptase mRNA for Therapy of Traumatic Brain Injury.

A traumatic brain injury (TBI) disrupts regular brain function, often resulting from head trauma, impacting nearly 3 million individuals in the United States annually. This condition can lead to significant cognitive impairments and, in severe cases, fatalities. Recent research has uncovered a connection between TBI and shortened telomeres, which are protective structures found at the ends of chromosomes, safeguarding genetic information. In this undertaking, our objective is to pioneer a groundbreaking approach for administering mRNA therapeutics, with the goal of extending telomeres in brain cells. This innovation aims to restore both motor and cognitive functions in individuals recovering from TBI.

Funding: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE Grant.

6. Precision-based microbiota therapy for Brain Injuries and Alzheimer’s disease.

Gut microbiota are an essential neuromodulator of gut-brain axis signaling and can impact brain inflammation and outcome after ischemic injury. Several studies have shown that microbiota composition, diversity, and richness can influence anxiety and depressive behaviors. The Villapol Lab has recently been focused on how TBI affects the function of peripheral systems and is studying how the brain injury alters the microbiome and the resultant impact on TBI-induced affective disorders.

7. Spaceflight effects on the gut-brain-axis and immune function.

Exposure to spaceflight conditions can substantially alter the gut microbiome, potentially impacting cognitive abilities and the health of the immune system. In our animal model, we expect to observe significant microbial imbalances, gastrointestinal inflammation, and neuroendocrine changes. Our research aims to determine if the radiation experienced during space travel contributes to cognitive impairments through gut dysbiosis. Additionally, we will explore if systemic inflammation influences neuroendocrine communication via the gut-brain axis.

Marissa Burke is working on this exciting project as part of her Ph.D.

8. Exploring Microbial Signatures for Neurological Manifestations in Long COVID Patients.

Long-COVID in children and adolescents: a systematic review and meta-analyses. Lopez-Leon S, Wegman-Ostrosky T, Ayuzo Del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S. Sci Rep. 2022 Jun 23;12(1):9950. doi: 10.1038/s41598-022-13495-5. PMID: 35739136 Free PMC article.

More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, Cuapio A, Villapol S. Sci Rep. 2021 Aug 9;11(1):16144. doi: 10.1038/s41598-021-95565-8. PMID: 34373540

9. CRISPR-lipid nanoparticles-based treatment for traumatic brain injury.

10. Exploring novel synergies between gut microbiome alterations after deep brain stimulation and cellular transplantation as a potential treatment of Parkinson’s disease and Traumatic Brain Injury.